This invention relates to novel condensed tetracyclic hetero-ring compounds having action in inhibiting strongly and highly selectively cyclic GMP-phosphodiesterase (hereinafter abbreviated as cGMP-PDE), featuring high safety, processes for producing such compounds, pharmaceuticals containing at least one of such compounds as an active ingredient, in particular, agents for preventing and/or treating pulmonary hypertension, ischemic heart diseases, erectile dysfunction, female sexual dysfunction or diseases against which the cGMP-PDE inhibition is effective, and intermediates useful for the production of the condensed tetracyclic hetero-ring compounds.
The identity of vascular endothelial cell derived relaxing factors has been found to be nitric oxide (hereinafter abbreviated as NO) which, like nitroglycerin used to treat angina pectoris, manifests its vascular relaxing action as mediated by the increase in cyclic GMP (hereinafter abbreviated as cGMP). Briefly, nitrites-like relaxing factors exist endogenously and counteract catecholamine and other endogenous vasoconstricting factors to adjust the tone of blood vessels and contribute to the retention of adequate blood flow. Therefore, the decrease in NO or cGMP is believed to enhance vasotonia and reduce the blood flow in tissue, eventually causing circulatory disorders or ischemic heart diseases. Increase in vasotonia resulting from damage to coronary endothelial cells which are in the class of NO producing cells is believed to induce insufficiency in the blood flow in myocardial tissue, thereby causing anginal attacks. This results from disorders in the NO-cGMP system working as an endogenous relaxing factor. The vasodilating action of nitrites depends on the diameter of blood vessels for the degree of relaxation and because of their active site specificity (i.e., thicker coronary arteries are relaxed more intensely), nitrites have so far been in common use. However, the nitrites have a disadvantage in that their action is transient and attenuated during prolonged use. In addition, it has been pointed out that among vasodilators, adenosine enhancers such as dipyridamole which dilate narrow portions of coronary arteries to increase the coronary blood flow increase the myocardial blood flow at normal sites rather than at the lesion, thereby aggravating the ischemia (this phenomenon is generally referred to as xe2x80x9cstealxe2x80x9d) and, hence, showing side effects such as aggravation of angina pectoris and pectoralgia.
While no effective therapeutics have been available for the various pathogenic conditions that manifest pulmonary hypertension, it has recently been reported that NO gas inhalation therapy has certain utility. Since NO gas relaxes blood vessels and lower the pulmonary arterial pressure through the increase in cGMP, it is anticipated that activation of the cGMP producing system dilates selectively pulmonary arteries in the pulmonary circulation, thereby contributing to the treatment of pulmonary hypertension. Calcium blockers and many other vasodilating drugs have so far been used in attempts to treat pulmonary hypertension, none have been commercialized since every one of them is more potent in lowering the systemic blood pressure than the pulmonary arterial pressure. An oxygen therapy has been verified to be effective in achieving improvements after its application. However, oxygen intoxication occurs as a serious side effect and the occurrence of pulmonary lesions such as pulmonary edema and fibrosis has been reported with patients who were on prolonged oxygen therapy at home. The NO gas inhalation therapy is not an exception and the NO gas used in this therapy is one of the air pollutants NOx and will easily generate NO2 in the presence of oxygen, thereby potentially causing adverse effects on the airway and lungs; hence, utmost care is required in applying the NO gas and many problems are involved in its prolonged use. On the other hand, suppressing the cGMP degradation system is believed another way to maintain the concentration of cGMP, thereby allowing for selective decrease in the pulmonary arterial pressure. Briefly, an inhibitor of phosphodiesterase (hereinafter abbreviated as PDE) which is an enzyme catalyzing specific hydrolyzation of cyclic GMP holds promise as a new therapeutic free from the aforementioned side effects.
With the inhibition of PDE, cGMP increases, possibly leading to the treatment of these diseases. As of today, PDE has been verified to exist in at least seven isozyme types (Physiological Reviews, 75, 725-748, 1995). Of these, five types of isozymes distribute in many diverse tissues. Two isozymes are capable of selective hydrolyzation of cGMP and they are PDE type I (calmodulin-dependent PDE) and PDE type V (cGMP-PDE). On the other hand, PDE types III and IV hydrolyse cyclic AMP (hereinafter abbreviated as cAMP) selectively and PDE type II has no substrate selectivity. If the last three isozymes are inhibited, cAMP is increased to cause various obvious side effects including enhanced myocardial contraction and heart rate and depression of systemic blood pressure. Among other things, it is well known that with the inhibition of type III PDE, cAMP increases resulting in enhanced myocardial contraction. It has been also reported that increased cGMP in cardiac muscle reduced myocardial contraction but the distribution of PDE type V has not been recognized in cardiac muscle. Furthermore, PDE type VI is distributed in the retina, and it is expected that the inhibition of this PDE type VI will cause defect in vision such as changes in blue/green color and increased sensitivity to light. Therefore, it is anticipated that selective inhibition of PDE type V will produce selective action that is limited in the decrease in systemic blood pressure and side effects on the heart and the retina. It has recently been found that NO releasing compounds show an inhibition of vascular smooth muscle cell proliferation with the intermediary of cGMP. For example, Garg et al. (J. Clin. Invest., 83, 1774-1777, 1989) and Nakaki et al. (Eur. J. Pharmacol., 189, 347-353, 1990) reported that the proliferation of cultured vascular smooth muscle cells isolated from aortic media in rats was suppressed by the treatment of NO releasing compounds nitroprusside, nitroglycerin, isosorbide dinitrate or 8-bromo-cGMP. Therefore, it is suggested that increased cGMP could suppress the proliferation of vascular smooth muscle cells in arteriosclerosis and post-PTCA restenosis. It is also known that the NO-cGMP system is involved in the mechanism of penile erection. When the sexual center in the brain is excited by sexual stimulation from the eyes or ears or by direct stimulation of the penis, the stimulation is transmitted to the nerves in corpus cavernosum penis via parasympathetic pelvic nerves, whereupon acetylcholine, vasoactive intestinal peptides and nitrogen monoxide (hereinafter abbreviated as NO) are released from the corpus cavernosum to relax the smooth muscle forming the valve structure in the spiral artery so that the arterial blood supplied from the penile deep artery and dorsal artery suddenly flows into the cavities of corpora cavernosa, causing the pressure in the corpus cavernosum penis to rise so that the fibrous trabeculae that have relaxed under the action of acetylcholine, vasoactive intestinal peptides and NO clog the flux veins or the cavities of corpora cavernosa will themselves increase in volume. In addition, the tension under the pressure of the tunica albuginea compresses the veins running obliquely across the tunica albuginea to obstruct the blood outflow. As the result, blood stays within the cavities of corpora cavernosa and the tunica albuginea becomes rigid under tension to establish penile erection.
It has been unravelled that the entity of the vascular endothelial cell derived relaxing factor is NO and develops its vasohypotonic action with the intermediary of an increased cGMP level. Therefore, it is postulated that suppressing the CGMP decomposing system is another way to maintain the CGMP level and achieve selective erection.
The cGMP-PDE inhibitors so far disclosed in the art include pyrazolopyrimidone derivatives (see EP-A-526004), purinone derivatives (JP-A 2-88577), phenylpyrimidone derivatives (JP-A 2-295978), quinazoline derivatives (JP-A 6-192235 and JP-A 7-10843 and WO 93/12095) and phthalazine derivatives (WO 96/05176). However, there is no prior art disclosure of the fact that compounds such as the ones claimed in the present invention which have a condensed tetracyclic hetero-ring have the cGMP-PDE inhibitory action. As for the PDE isozyme selectivity, EP-A 526004 and WO 93/12095 teach isozyme selectivity between types V and III but the selectivity has not yet been commercialized in clinical fields to demonstrate a satisfactory action.
Recently, there is a report on the clinical test results of a therapeutic agent for impotence through oral administration of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one citrate (hereinafter, abbreviated as sildenafil) which is a PDE type V inhibitor (cf. Drugs of the Future, volume 22, page 138-143, 1997). However side effect such as headache, flushing, dyspepsia, muscular pain, and visual. disability were reported.
Referring to condensed tetracyclic hetero-ring compounds, Ohmoto et al., Chem. Pharm. Bull., 36, 11, 4588-4592, 1988 and Song et al., Chem. Pharm. Bull., 32, 5, 1872-1877, 1984 have reported the cAMP-PDE inhibitory activity of canthin-6-one derivatives. JP-A 60-12791 teaches the phosphodiesterase inhibitory activity of 5-hydroxymethyl-canthin-6-one. However, these compounds have different structures than the compounds of the invention and there has been no teaching at all as to whether they have a selective cGMP-PDE inhibitory action.
An object, therefore, of the invention is to provide novel compounds that have high isozyme selectivity and potent cGMP-PDE inhibitory action and that cause less side effects to feature high safety.
Other objects of the invention are to provide processes for producing such compounds, intermediates useful for producing them, as well as pharmaceuticals and pharmaceutical compositions containing said compounds. In particular, the invention aims at providing agents for preventing and/or treating pulmonary hypertension, ischemic heart diseases, erectile dysfunction, female sexual dysfunction or diseases against which the cGMP-PDE inhibitory action is effective, said agents having solved at least one of the aforementioned problems with the prior art.
The present inventors conducted intensive studies with a view to obtaining drugs that are capable of potent and selective inhibition of type V PDE while featuring high safety. As a result, they found that novel condensed tetracyclic hetero-ring compounds and salts thereof have potent and selective type V PDE inhibiting activity and this finding has eventually led to the accomplishment of the present invention.
According to its first aspect, the invention provides compounds represented by the following formula (I) or salts thereof or pharmaceuticals containing said compounds or salts as an active ingredient: 
where A represents a single bond, a methylene group, a carbonyl group, an oxygen atom, a group: xe2x80x94SOnxe2x80x94 (n is 0-2), a group: xe2x80x94N(R6)xe2x80x94, a group: xe2x80x94CR7(OR8)xe2x80x94 or a group: xe2x80x94C(xe2x95x90Nxe2x80x94R9)xe2x80x94; Y1-Y3 and Z1-Z4 represent each a methine group or a nitrogen atom; R1 represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected carboxymethyl group, an alkoxycarbonyl group having 1-4 carbon atoms, a carbamoyl group, an acetylamino group, a 3-carboxy-1-propenyl group, a 2-hydroxypentyloxy group, a 2,2-diethoxyethoxy group, an optionally protected hydroxyl group, an optionally protected mercapto group, a straight- or branched-chain alkanoyloxy group having 1-4 carbon atoms, a carbonyloxy group substituted by a phenyl group or a pyridyl group, a straight- or branched-chain alkyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group, an amino group which may be mono- or disubstituted by an alkyl group having 1-4 carbon atoms, an alkylthio group having 1-3 carbon atoms which may be monosubstituted by any group selected from the group consisting of a hydroxyl group, a carboxyl group, a phenyl group and a pyridyl group, a 1-methyl-hexahydroazepin-4-yl-oxy group, or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
(where Q represents a hydrogen atom, a carboxyl group, an alkoxy group having 1 or 2 carbon atoms which may be substituted by one hydroxyl group, an alkoxycarbonyl group having 1-6 carbon atoms, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a piperidinylcarbonyl group which may be substituted by one carboxyl group or alkoxycarbonyl group having 1 or 2 carbon atoms, a morpholylcarbonyl group, a hydroxyl group, a mercapto group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may be the same or different, or may combine each other to form a ring), a phenyl group which may be mono- or disubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a pyridyl group which may be monosubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a pyrazinyl group, a pyrimidinyl group, a furyl group, a thienyl group, an oxadiazolyl group, a 4-methoxyphenoxy group, a 1-benzotriazolyl group, a 4-morpholinyl group, or 2-benzimidazolyl group; n is 1-6); R2 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected mercapto group, an optionally protected amino group, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an optionally protected carboxyl group, a 4-morpholylacetyl group, a straight- or branched-chain alkanoyloxy group having 1-4 carbon atoms, a straight- or branched-chain alkanoyl group having 1-4 carbon atoms, a straight- or branched-chain alkyl group having 1-4 carbon atoms, an alkylthio group having 1-3 carbon atoms which may be monosubstituted by any group selected from the group consisting of a hydroxyl group, a carboxyl group, a phenyl group and a pyridyl group, or a straight- or branched-chain alkoxy group having 1-4 carbon atoms which may be monosubstituted by any group selected from the group consisting of an alkoxycarbonyl group having 1-4 carbon atoms, a hydroxyl group, a carboxyl group, a phenyl group and a pyridyl group; R3 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R4 represents a hydrogen atom, a halogen atom, a group: xe2x80x94Mxe2x80x94G (where M represents an oxygen atom, an imino group or a group: xe2x80x94N(CH3)xe2x80x94, and G represents a phenyl group which may be mono- or disubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group), an alkyl group having 1 or 2 carbon atoms which may be substituted by a cyclic alkyl group having 3-6 carbon atoms, a benzyl group which may be mono- or disubstituted in the benzene ring by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group,)a pyridylmethyl group which may be monosubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a morpholylmethyl group, a triazolylmethyl group, a furylmethyl group, a thienylmethyl group, a pyrimidinylmethyl group, a pyrazinylmethyl group, a pyrrolylmethyl group, an imidazolylmethyl group, a quinolylmethyl group, an indolylmethyl group, a naphthylmethyl group, a benzoyl group or an xcex1-hydroxybenzyl group; R5 represents a hydrogen atom or a methyl group; R6 represents a hydrogen atom, a straight- or branched-chain alkyl group having 1-4 carbon atoms or a straight- or branched-chain alkanoyl group having 1-4 carbon atoms; R7 represents a hydrogen atom or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R8 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms, provided that the alkoxy group as R7 and the alkyl group as R8 may combine to form a ring; R9 represents a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, a carboxymethyloxy group or a group: xe2x80x94NR10R10 (the two R10s may be the same or different); R10 represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms; provided that are limited the compounds wherein, when A represents a single bond, and all of Y1-Y3 and Z1-Z4 represent a methine group, R1 represents a 1-methyl-hexahydroazepin-4-yl-oxy group, or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
(where Q represents a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; R24 may not be hydrogen atom at the same time, or may combine each other to form a ring), a phenyl group which was mono- or disubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a pyridyl group which was monosubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group and a carbamoyl group, a 1-benzotriazolyl group, a 4-morpholinyl group, or 2-benzimidazolyl group; n is 1-6); or R2 represents a straight- or branched-chain alkoxy group having 1-4 carbon atoms which was monosubstituted by any group selected from the group consisting of a hydroxyl group, a carboxyl group, a phenyl group and a pyridyl group; or R4 represents a group: xe2x80x94Mxe2x80x94G (where M represents an oxygen atom, an imino group or a group: xe2x80x94N(CH3)xe2x80x94, and G represents a phenyl group which was mono- or disubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group), a benzyl group which was mono- or disubstituted in the benzene ring by any group selected from the group consisting of a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a pyridylmethyl group which was monosubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, a hydroxymethyl group and an acetoxymethyl group; and it is also noted that the compounds other than the above described limited compounds represented by the formula (I), if the compounds are useful as a pharmaceutical agent of the present invention, the other compounds are included in the present pharmaceutical invention, and that are excluded the compounds wherein, A represents a single bond, Y1 and Y2 represent a methine group, Y3 represents a nitrogen atom, Z1-Z4 represent a methine group, R1, R2 and R3 represent respectively a hydrogen atom, and R4 represents a hydrogen atom and R5 represents a hydrogen atom or a methyl group, or R4 represents an ethyl group and R5 represents a hydrogen atom, or R4 represents a chlorine atom and R5 represents a methyl group; the compounds wherein A represents a sulfur atom, and all of Y1-Y3 and Z1-Z4 represent a methine group, R1, R2, R3 and R5 represent respectively a hydrogen atom, and R4 represents a hydrogen atom, a benzyl group, a 4-methoxybenzyl group, a 4-dimethylaminobenzyl group, a 4-chlorobenzyl group, a 3-nitrobenzyl group, or a bromine atom; the compounds wherein A represents an oxygen atom, and all of Y1-Y3 and Z1-Z4 represent a methine group, R1, R2, R3 and R5 represent respectively a hydrogen atom, and R4 represents a hydrogen atom, a benzyl group, a 4-methoxybenzyl group, a 4-dimethylaminobenzyl group, a 4-chlorobenzyl group, or a 3-nitrobenzyl group; the compounds wherein A represents a carbonyl group, and all of Y1-Y3 and Z1-Z4 represent a methine group, R2, R3, R4 and R5 represent respectively a hydrogen atom, and R1 represents a methoxy group at position 5; the compounds wherein A represents a carbonyl group, and all of Y1-Y3 and Z1-Z4 represent a methine group, R1, R4 and R5 represent respectively a hydrogen atom, and one of R2 and R3 represents a hydrogen atom and the other one of R2 and R3 represents a methoxy group at position 9; the compounds wherein A represents a group: SOn (n is 1), and all of Y1-Y3 and Z1-Z4 represent a methine group, and R1, R2, R3, R4 and R5 represent respectively a hydrogen atom, and it is noted that as to the above described compounds excluded from the compounds represented by the formula (I), if the compounds are useful as a pharmaceutical agent of the present invention, the excluded compounds are included in the present pharmaceutical invention.
The preferred substituents in the compounds represented by the above formula (I) or the preferred combinations thereof are shown below but the invention is by no means limited thereto.
Speaking of R1, it is preferably substituted at position 2 in the case of the formula (I)-a and position 5 in the case of the formula (I)-b, and is preferably a hydroxyl group or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 1-6 carbon atoms, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a hydroxyl group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may be the same or different, or may combine each other to form a ring), a phenyl group, a pyridyl group which may be monosubstituted by a hydroxymethyl group, an acetoxymethyl group, an alkyl group having 1-4 carbon atoms or an alkoxycarbonyl group having 1 or 2 carbon atoms, pyrazinyl group, a pyrimidinyl group, or a 1-benzotriazolyl group; n is 1-4.
More preferably, R1 is substituted at position 2 in the case of the formula (I)-a and position 5 in the case of the formula (I)-b, and is either a hydroxyl group or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a hydrogen atom, a carboxyl group, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a hydroxyl group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may be the same or different, or may combine each other to form a ring), a phenyl group, a pyridyl group which may be monosubstituted by a hydroxymethyl group, an acetoxymethyl group, an alkyl group having 1-4 carbon atoms or an alkoxycarbonyl group having 1 or 2 carbon atoms, a pyrazinyl group, a pyrimidinyl group, or a 1-benzotriazolyl group; n is 1-4.
Preferably, R2 and R3 are not a hydrogen atom at the same time; it is preferred that R2 is substituted at position 9 or 10 and is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group or a straight- or branched-chain alkoxy group having 1-4 carbon atoms and that R3 is a hydrogen atom.
Preferably, R4 is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, a pyrimidinylmethyl group or a pyridylmethyl group which may be substituted by a methyl group. Further, it is more preferred that R4 is a methyl group, a pyrimidinylmethyl group or a pyridylmethyl group. Preferably, R5 is a hydrogen atom.
The preferred combinations of the substituents are as follows: R1 is substituted at position 2 in the formula (I)-a and position 5 in the formula (I)-b, and is either a hydroxyl group or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a hydrogen atom, a carboxyl group, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a hydroxyl group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may be the same or different, or may combine each other to form a ring), a phenyl group, a pyridyl group which may be monosubstituted by a hydroxymethyl group, an acetoxymethyl group, an alkyl group having 1-4 carbon atoms or an alkoxycarbonyl group having 1 or 2 carbon atoms, a pyrazinyl group, a pyrimidinyl group, or a 1-benzotriazolyl group; n is 1-4; R2 is a halogen atom, a cyano group or a trifluoromethyl group which is substituted at position 9 or 10; R3 is a hydrogen atom; R4 is a methyl group, a pyrimidinylmethyl group or a pyridylmethyl group; and R5 is a hydrogen atom.
The specific individual compounds of the invention include:
(1) 10-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
(2) 9-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
(3) 10-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(4) 9-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(5) 10-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(6) 9-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(7) 7-acetyl-10-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(8) 7-acetyl-9-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(9) 10-bromo-5-(3-hydroxypropyloxy)-7-methyl-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(10) 9-bromo-5-(3-hydroxypropyloxy)-7-methyl-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(11) 10-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
(12) 9-bromo-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
(13) 10-bromo-7-hydroxy-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(14) 9-bromo-7-hydroxy-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(15) 10-bromo-7-(hydroxyimino)-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(16) 9-bromo-7-(hydroxyimino)-5-(3-hydroxypropyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(17) 9-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H-indolo[3,2,1-de][1,5]naphthyridin-4-one
(18) 10-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H-indolo[3,2,1-de][1,5]naphthyridin-4-one
(19) 9-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H[7]-azaindolo[3,2,1-ij]quinolin-4-one
(20) 10-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H[7]-azaindolo[3,2,1-ij]quinolin-4-one
(21) 9-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H[5]-azaindolo[3,2,1-ij]quinolin-4-one
(22) 10-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H[6]-azaindolo[3,2,1-ij]quinolin-4-one
(23) 9-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H[4]-azaindolo[3,2,1-ij]quinolin-4-one
(24) 10-bromo-2-(3-hydroxypropyloxy)-5-(3-pyridylmethyl)-4H[4]-azaindolo[3,2,1-ij]quinolin-4-one
 less than Axe2x95x90O greater than 
(25) 10-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
(26) 5-(1-benzotriazolylmethyloxy)-10-bromo-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
(27) 10-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
(28) 9-bromo-5-(3-pyridylmethyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
(29) 5-(1-benzotriazolylmethyloxy)-9-bromo-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
(30) 9-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenoxazin-3-one
 less than Axe2x95x90S greater than 
(31) 10-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(32) 5-(1-benzotriazolylmethyloxy)-10-bromo-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(33) 10-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(34) 9-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(35) 9-bromo-5-(1-benzotriazolylmethyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(36) 9-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
 less than Axe2x95x90NH greater than 
(37) 10-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(38) 5-(1-benzotriazolylmethyloxy)-10-bromo-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(39) 10-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(40) 9-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(41) 9-bromo-5-(1-benzotriazolylmethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(42) 9-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
 less than Axe2x95x90Nxe2x80x94Ac greater than 
(43) 7-acetyl-10-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(44) 7-acetyl-5-(1-benzotriazolylmethyloxy)-10-bromo-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(45) 7-acetyl-10-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(46) 7-acetyl-9-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(47) 7-acetyl-5-(1-benzotriazolylmethyloxy)-9-bromo-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(48) 7-acetyl-9-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
 less than Axe2x95x90Nxe2x80x94Me greater than 
(49) 10-bromo-7-methyl-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(50) 5-(1-benzotriazolylmethyloxy)-10-bromo-7-methyl-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(51) 10-bromo-7-methyl-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(52) 9-bromo-7-methyl-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(53) 5-(1-benzotriazolylmethyloxy)-9-bromo-7-methyl-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
(54) 9-bromo-7-methyl-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]phenazin-3-one
 less than Axe2x95x90CO greater than 
(55) 10-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
(56) 5-(1-benzotriazolylmethyloxy)-10-bromo-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
(57) 10-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
(58) 9-bromo-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
(59) 5-(1-benzotriazolylmethyloxy)-9-bromo-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
(60) 9-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3,7-dione
 less than Axe2x95x90CHxe2x80x94OH greater than 
(61) 10-bromo-7-hydroxy-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(62) 5-(1-benzotriazolylmethyloxy)-10-bromo-7-hydroxy-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(63) 10-bromo-7-hydroxy-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(64) 9-bromo-7-hydroxy-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(65) 5-(1-benzotriazolylmethyloxy)-9-bromo-7-hydroxy-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(66) 9-bromo-7-hydroxy-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
 less than Axe2x95x90Nxe2x80x94OH greater than 
(67) 10-bromo-7-(hydroxyimino)-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(68) 5-(1-benzotriazolylmethyloxy)-10-bromo-7-(hydroxyimino)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(69) 10-bromo-7-(hydroxyimino)-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(70) 9-bromo-7-(hydroxyimino)-2-(3-pyridylmethyl)-5-(3-pyridylmethyloxy)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(71) 9-bromo-7-(hydroxyimino)-5-(1-benzotriazolylmethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(72) 9-bromo-7-(hydroxyimino)-5-(2-(1-piperidyl)ethyloxy)-2-(3-pyridylmethyl)-3H,7H-pyrido[3,2,1-de]acridin-3-one
(73) 10-bromo-5-hydroxy-2-(3-pyridylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(74) 2-benzyl-10-bromo-5-(3-hydroxypropyloxy)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(75) 2-benzyl-10-bromo-5-(3-pyridylmethyloxy)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(76) 2-benzyl-10-bromo-5-(1-benzotriazolylmethyloxy)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(77) 2-benzyl-10-bromo-5-(2-(1-piperidyl)ethyloxy)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(78) 10-bromo-5-(3-hydroxypropyloxy)-2-(5-pyrimidinylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(79) 10-bromo-5-(3-pyridylmethyloxy)-2-(5-pyrimidinylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(80) 5-(1-benzotriazolylmethyloxy)-10-bromo-2-(5-pyrimidinylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one
(81) 10-bromo-5-(2-(1-piperidyl)ethyloxy)-2-(5-pyrimidinylmethyl)-3H-pyrido[3,2,1-kl]phenothiazin-3-one.
According to its second aspect, the present invention provides compounds represented by the above formula (I) where all of Y1-Y3 and Z1-Z4 represents a methine group, or salts thereof. A, the substituents and R1-R5 in this formula as well as the substituents R6-R10 defined in A are the same as in the above formula (I).
The preferred substituents in this particular case or the preferred combinations thereof are shown below but the invention is by no means limited thereto.
Speaking of R1, it is preferably substituted at position 2 in the case of the formula (I)-a and position 5 in the case of the formula (I)-b, and is preferably a hydroxyl group or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 1-6 carbon atoms, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a hydroxyl group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; R24 may not be hydrogen atom at the same time, or may combine each other to form a ring), a phenyl group, a pyridyl group which may be monosubstituted by a hydroxymethyl group, an acetoxymethyl group, an alkyl group having 1-4 carbon atoms or an alkoxycarbonyl group having 1 or 2 carbon atoms, a pyrazinyl group, a pyrimidinyl group, or a 1-benzotriazolyl group; n is 1-4.
More preferably, R1 is substituted at position 2 in the case of the formula (I)-a and position 5 in the case of the formula (I)-b, and is either a hydroxyl group or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a hydrogen atom, a carboxyl group, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a hydroxyl group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; R24 may not be hydrogen atom at the same time, or may combine each other to form a ring), a phenyl group, a pyridyl group which may be monosubstituted by a hydroxymethyl group, an acetoxymethyl group, an alkyl group having 1-4 carbon atoms or an alkoxycarbonyl group having 1 or 2 carbon atoms, a pyrazinyl group, a pyrimidinyl group, or a 1-benzotriazolyl group; n is 1-4.
Preferably, R2 and R3 are not a hydrogen atom at the same time; it is preferred that R2 is substituted at position 9 or 10 and is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group or a straight- or branched-chain alkoxy group having 1-4 carbon atoms and that R3 is a hydrogen atom.
Preferably, R4 is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, a pyrimidinylmethyl group or a pyridylmethyl group which may be substituted by a methyl group. Further, it is more preferred that R4 is a methyl group, a pyrimidinylmethyl group or a pyridylmethyl group. Preferably, R5 is a hydrogen atom.
The preferred combinations of the substituents are as follows: R1 is substituted at position 2 in the formula (I)-a and position 5 in the formula (I)-b, and is either a hydroxyl group or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a hydrogen atom, a carboxyl group, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a hydroxyl group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may be the same or different, or may combine each other to form a ring), a phenyl group, a pyridyl group which may be monosubstituted by a hydroxymethyl group, an acetoxymethyl group, an alkyl group having 1-4 carbon atoms or an alkoxycarbonyl group having 1 or 2 carbon atoms, a pyrazinyl group, a pyrimidinyl group, or a 1-benzotriazolyl group; n is 1-4; R2 is a halogen atom, a cyano group or a trifluoromethyl group which is substituted at position 9 or 10; R3 is a hydrogen atom; R4 is a methyl group, a pyrimidinylmethyl group or a pyridylmethyl group; and R5 is a hydrogen atom.
According to its third aspect, the invention provides compounds of the above formula (I) where all of Y1-Y3 and Z1-Z4 represent a methine group, A is an oxygen atom, a group: xe2x80x94SOnxe2x80x94 (n is 0-2), or a group: xe2x80x94N(R6)xe2x80x94, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). In this particular case, preferably A is a group: xe2x80x94SOnxe2x80x94 (n is 0-2), and then more preferably A is a sulfur atom. The substituents that are preferred in this particular case or preferred combinations thereof are the same as its second aspect but the invention is by no means limited thereto.
According to its fourth aspect, the invention provides compounds of the above formula (I) where all of Y1-Y3 and Z1-Z4 represent a methine group, A is a carbonyl group, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as its second aspect but the invention is by no means limited thereto.
According to its fifth aspect, the invention provides compounds of the above formula (I) where all of Y1-Y3 and Z1-Z4 represent a methine group, A is a single bond, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as its second aspect but the invention is by no means limited thereto.
Speaking of R1, it is preferably substituted at position 2, and is preferably a hydroxyl group, a 1-methyl-hexahydroazepin-4-yl-oxy group, or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 1-6 carbon atoms, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a hydroxyl group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may not be hydrogen atom at the same time, or may combine each other to form a ring), a pyrazinyl group, a pyrimidinyl group, a 1-benzotriazolyl group, a 4-morpholinyl group, or 2-benzimidazolyl group; n is 1-4.
More preferably, R1 is substituted at position 2, and is either a hydroxyl group or represented by the following formula (II):
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may not be hydrogen atom at the same time, or may combine each other to form a ring); n is 1-4.
Preferably, R2 and R3 are not a hydrogen atom at the same time; it is preferred that R2 is substituted at position 9 or 10 and is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group or a straight- or branched-chain alkoxy group having 1-4 carbon atoms and that R3 is a hydrogen atom.
Preferably, R4 is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, a pyrimidinylmethyl group or a pyridylmethyl group which may be substituted by a methyl group. Further, it is more preferred that R4 is a methyl group, a pyrimidinylmethyl group or a pyridylmethyl group. Preferably, R5 is a hydrogen atom.
The preferred combinations of the substituents are as follows: R1 is substituted at position 2, and is either a hydroxyl group or represented by the following formula (II):
xe2x80x83xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83(II)
where Q represents a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may be the same or different, or may combine each other to form a ring); n is 1-4; R2 is a halogen atom, a cyano group or a trifluoromethyl group which is substituted at position 9 or 10; R3 is a hydrogen atom; R4 is a methyl group, a pyrimidinylmethyl group or a pyridylmethyl group; and R5 is a hydrogen atom.
According to its sixth aspect, the invention provides compounds of the above formula (I) where Y1 is a nitrogen atom and all of Y2, Y3 and Z1-Z4 represent a methine group, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as set forth above.
According to its seventh aspect, the invention provides compounds of the above formula (I) where Y3 is a nitrogen atom and all of Y1, Y2 and Z1-Z4 represent a methine group, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as set forth above.
According to its eighth aspect, the invention provides compounds of the above formula (I) where Z1 is a nitrogen atom and all of Y1-Y3 and Z2, Z3 and Z4 represent a methine group, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as set forth above.
According to its ninth aspect, the invention provides compounds of the above formula (I) where Z2 is a nitrogen atom, all of Y1-Y3 and Z1, Z3 and Z4 represent a methine group, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as set forth above.
According to its tenth aspect, the invention provides compounds of the above formula (I) where Z3 is a nitrogen atom, all of Y1-Y3 and Z1, Z2 and Z4 represent a methine group, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as set forth above.
According to its eleventh aspect, the invention provides compounds of the above formula (I) where Z4 is a nitrogen atom, all of Y1-Y3 and Z1, Z2 and Z3 represent a methine group, or salts thereof. The other elements of the formula, namely, A, substituents R1-R5, and substituents R6-R10 defined in A are identical to those defined for the above formula (I). The substituents that are preferred in this particular case or preferred combinations thereof are the same as set forth above.
According to its twelfth aspect, the invention provides compounds of the formula (I) where the total number of nitrogen atoms in Y1-Y3 and Z1-Z4 is 0, A is a methylene group, a carbonyl group, an oxygen atom, a group: xe2x80x94SOnxe2x80x94 (n is 0-2), a group: xe2x80x94N(R6)xe2x80x94, a group: xe2x80x94CR7(OR8)xe2x80x94 or a group: xe2x80x94C(xe2x95x90Nxe2x80x94R9)xe2x80x94, or salts thereof . In this particular case, A, substituents R1-R5, and R6-R10 defined in A are the same as defined for the above formula (I).
According to its thirteenth aspect, the invention provides compounds of the formula (I) where the total number of nitrogen atoms in Y1-Y3 and Z1-Z4 is 1, and A is a single bond, or salts thereof. In this particular case, A, substituents R1-R5, and R6-R10 defined in A are the same as defined for the above formula (I).
According to its fourteenth aspect, the invention provides compounds of the formula (I) where the total number of nitrogen atoms in Y1-Y3 and Z1-Z4 is 2, and A is a single bond, a methylene group, a carbonyl group, an oxygen atom, a group: xe2x80x94SOnxe2x80x94 (n is 0-2), a group: xe2x80x94N(R6)xe2x80x94, a group: xe2x80x94CR7(OR8)xe2x80x94 or a group: xe2x80x94C(xe2x95x90Nxe2x80x94R9)xe2x80x94, or salts thereof. In this particular case, A, substituents R1-R5, and R6-R10 defined in A are the same as defined above.
According to its fifteenth aspect, the invention provides intermediates represented by the following formula (VI) or salts thereof which are useful for the synthesis of compounds of the above formula (I) or salts thereof: 
(where A represents a single bond, a methylene group, a carbonyl group, an oxygen atom, a group: xe2x80x94SOnxe2x80x94 (n is 0-2), a group: xe2x80x94N(R6)xe2x80x94, a group: xe2x80x94CR7(OR8)xe2x80x94 or a group: xe2x80x94C(xe2x95x90Nxe2x80x94R9)xe2x80x94; Y1-Y3 and Z1-Z4 represent each a methine group or a nitrogen atom; R5 represents a hydrogen atom or a methyl group; R6 represents a hydrogen atom, a straight- or branched-chain alkyl group having 1-4 carbon atoms or a straight- or branched-chain alkanoyl group having 1-4 carbon atoms; R7 represents a hydrogen atom or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R8 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms, provided that the alkoxy group as R7 and the alkyl group as R8 may combine to form a ring; R9 represents a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, a carboxymethyloxy group or a group: xe2x80x94NR10R10 (the two R10s may be the same or different); R10 represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms; R11 represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected carboxymethyl group, an alkoxycarbonyl group having 1-4 carbon atoms, a carbamoyl group, an acetylamino group, an optionally protected hydroxyl group, an optionally protected mercapto group, a straight- or branched-chain alkyl group having 1-4 carbon atoms which may optionally be substituted by one hydroxyl group, an amino group which may optionally be mono- or disubstituted by an alkyl group having 1-4 carbon atoms, an alkylthio group having 1-3 carbon atoms, or a straight-chain alkoxy group having 1-6 carbon atoms which may optionally be substituted by a 4-methoxyphenoxy group; R12 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected mercapto group, an optionally protected amino group, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an optionally protected carboxyl group, a straight- or branched-chain alkanoyl group having 1-4 carbon atoms, a straight- or branched-chain alkyl group having 1-4 carbon atoms, or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R13 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R19 represents a hydrogen atom, a halogen atom, a group: xe2x80x94Mxe2x80x94G (where M represents an oxygen atom, an imino group or a group: xe2x80x94N(CH3)xe2x80x94, and G represents a phenyl group which may be mono- or disubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group), an xcex1-hydroxybenzyl group, a methyl group or a halogenomethyl group; provided that are excluded the compounds wherein, when A represents a single bond, and all of Y1-Y3 and Z1-Z4 represent a methine group; the compounds wherein, A represents an oxygen atom or a group: xe2x80x94SOnxe2x80x94 (n is 0-2), all of Y1-Y3 and Z1-Z4 represent a methine group, and all of R5, R11, R12, R13and R19 represent respectively a hydrogen atom; the compounds wherein, A represents a sulfur atom, all of Y1-Y3 and Z1-Z4 represent a methine group, R5, R11 and R19 represent respectively a hydrogen atom, and one of R12 and R13 represents a hydrogen atom and the other one of R12 and R13 represents a fluorine atom, a chlorine atom or a bromine atom at position 10, or a chlorine atom at position 11; the compounds wherein, A represents a sulfur atom, all of Y1-Y3 and Z1-Z4 represent a methine group, R5, R11, R12 and R13 represent respectively a hydrogen atom, and R19 represents a bromine atom or a methyl group; the compounds wherein, A represents a sulfur atom, all of Y1-Y3 and Z1-Z4 represent a methine group, R5, R12, R13 and R19 represent respectively a hydrogen atom, and R11 represents a chlorine atom at position 4; the compounds wherein, A represents a sulfur atom, all of Y1-Y3 and Z1-Z4 represent a methine group, R5, R1, R13 and R19 represent respectively a hydrogen atom, and R12 represents a trifluoromethyl group at position 9, 10 or 11; the compounds wherein, A represents a sulfur atom, all of Y1-Y3 and Z1-Z4 represent a methine group, R5, R13 and R19 represent respectively a hydrogen atom, R11 represents a methyl group at position 4, and R12 represents a trifluoromethyl group at position 10; the compounds wherein, A represents a single bond, Y1 and Y2 represent a methine group, Y3 represents a nitrogen atom, Z1-Z4 represent a methine group, and all of R5, R11, R12, R13 and R19 represent respectively a hydrogen atom.)
According to its sixteenth aspect, the present invention provides a process for producing said derivative compounds of the above formula (I) in which a compound represented by the following formula (VI) or a salt thereof: 
(where A represents a single bond, a methylene group, a carbonyl group, an oxygen atom, a group: xe2x80x94SOnxe2x80x94 (n is 0-2), a group: xe2x80x94N(R6)xe2x80x94, a group: xe2x80x94CR7(OR8)xe2x80x94 or a group: xe2x80x94C(xe2x95x90Nxe2x80x94R9)xe2x80x94; Y1-Y3 and Z1-Z4 represent each a methine group or a nitrogen atom; R5 represents a hydrogen atom or a methyl group; R6 represents a hydrogen atom, a straight- or branched-chain alkyl group having 1-4 carbon atoms or a straight- or branched-chain alkanoyl group having 1-4 carbon atoms; R7 represents a hydrogen atom or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R8 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms, provided that the alkoxy group as R7 and the alkyl group as R8 may combine to form a ring; R9 represents a hydrogen atom, a hydroxyl group, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, a carboxymethyloxy group or a group: xe2x80x94NR10R10 (the two R10s may be the same or different); R10 represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms; R11 represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected carboxymethyl group, an alkoxycarbonyl group having 1-4 carbon atoms, a carbamoyl group, an acetylamino group, an optionally protected hydroxyl group, an optionally protected mercapto group, a straight- or branched-chain alkyl group having 1-4 carbon atoms which may optionally be substituted by one hydroxyl group, an amino group which may optionally be mono- or disubstituted by an alkyl group having 1-4 carbon atoms, an alkylthio group having 1-3 carbon atoms, or a straight-chain alkoxy group having 1-6 carbon atoms which may optionally be substituted by a 4-methoxyphenoxy group; R12 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected mercapto group, an optionally protected amino group, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an optionally protected carboxyl group, a straight- or branched-chain alkanoyl group having 1-4 carbon atoms, a straight- or branched-chain alkyl group having 1-4 carbon atoms, or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R13 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group or a straight- or branched-chain alkoxy group having 1-4 carbon atoms; R19 represents a hydrogen atom, a halogen atom, a group: xe2x80x94Mxe2x80x94G (where M represents an oxygen atom, an imino group or a group: xe2x80x94N(CH3)xe2x80x94, and G represents a phenyl group which may be mono- or disubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group), an xcex1-hydroxybenzyl group, a methyl group or a halogenomethyl group) is reacted optionally, under basic conditions, with an aldehyde derivative represented by the following formula (XVII):
R22xe2x80x94CHOxe2x80x83xe2x80x83(XVII)
(where R22 represents a hydrogen atom, a methyl group, a cyclic alkyl group having 3-6 carbon atoms, a phenyl group which may be mono- or disubstituted in the benzene ring by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a pyridyl group which may be monosubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a morpholyl group, a triazolyl group, a furyl group, a thienyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, an imidazolyl group, a quinolyl group, an indolyl group or a naphthyl group) and then the reaction product either in an isolated form or after dehydration to yield an enone which has the double bond subsequently isomerized in the ring, is subjected to an oxidation, either immediately or after reaction with phenol, aniline, N-methylaniline, triazole, imidazole, morpholine, etc. to derive a compound represented by the following formula (XIV): 
(where R4, R5, R11, R12, R13, Y1-Y3, Z1-Z4 and A as well as R6, R7, R8, R9 and R10 defined in A have the same meanings as defined above), said compound (XIV) is optionally subjected to a suitable substituent change and, after optional deprotection of R11, reacted with a reactive halogen derivative represented by the following formula (XVIII):
R23xe2x80x94Xxe2x80x83xe2x80x83(XVIII)
(where X is a halogen atom, R23 represents an alkoxycarbonyl group having 1-4 carbon atoms, a 3-carboxy-1-propenyl group, a 2,2-diethoxyethyl group, a straight- or branched-chain alkanoyl group having 1-4 carbon atoms, a carbonyl group substituted by a phenyl group or a pyridyl group, or a group: xe2x80x94(CH2)nxe2x80x94Q (where Q represents a hydrogen atom, a carboxyl group, an alkoxy group having 1 or 2 carbon atoms which may be substituted by one hydroxyl group, an alkoxycarbonyl group having 1-6 carbon atoms, a carbamoyl group which may be mono- or disubstituted by a hydroxymethyl group or an alkyl group having 1 or 2 carbon atoms, an alkanoyl group having 1-4 carbon atoms which may be substituted by one hydroxyl group or one mercapto group, a piperidinylcarbonyl group which may be substituted by one carboxyl group or alkoxycarbonyl group having 1 or 2 carbon atoms, a morpholylcarbonyl group, a hydroxyl group, a mercapto group, a group: xe2x80x94NR24R24 (R24 represents a hydrogen atom or an alkyl group having 1-4 carbon atoms; the two R24s may be the same or different, or may combine each other to form a ring), a phenyl group which may be mono- or disubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a pyridyl group which may be monosubstituted by any group selected from the group consisting of a halogen atom, a hydroxyl group, a mercapto group, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, an alkoxycarbonyl group having 1-4 carbon atoms, an acetylamino group, a carboxyl group, an amino group, a cyano group, a nitro group, an amino group mono- or disubstituted by a lower alkyl group, a carbamoyl group, an alkyl group having 1-4 carbon atoms, a hydroxymethyl group and an acetoxymethyl group, a pyrazinyl group, a pyrimidinyl group, a furyl group, a thienyl group, an oxadiazolyl group, a 4-methoxyphenoxy group, a 1-benzotriazolyl group, a 4-morpholinyl group, or 2-benzimidazolyl group; n is 1-6)) to yield a compound represented by the following formula (XV): 
(where R1, R4, R5, R12, R13, Y1-Y3, Z1-Z4 and A as well as R6, R7, R8, R9 and R10 defined in A have the same meanings as defined above), which is subjected to a suitable substituent change, or alternatively, the compound represented by the formula (XIV) is subjected to a suitable substituent change to yield a compound represented by the following formula (XVI): 
(where R2, R3, R4, R5, R11, Y1-Y3, Z1-Z4 and A as well as R6, R7, R8, R9 and R10 defined in A have the same meanings as defined above), which is optionally subjected to deprotection of R11 and reacted with the reactive halogen derivative represented by the formula (XVIII) so as to produce the compound represented by the following formula (I) or a salt thereof: 
(where R1, R2, R3, R4, R5, Y1-Y3, Z1-Z4 and A as well as R6, R7, R8, R9 and R10 defined in A have the same meanings as defined above).
According to its seventeenth aspect, the present invention provides agents for preventing or treating diseases against which the cGMP-PDE inhibitory action is effective in the presence of at least one of the compounds of the above formula (I) or salts thereof as an active ingredient.
According to its eighteenth aspect, the present invention provides agents for preventing or treating pulmonary hypertension which contain at least one of the compounds of the above formula (I) or salts thereof as an active ingredient.
According to its nineteenth aspect, the present invention provides agents for preventing or treating ischemic heart diseases which contain at least one of the compounds of the above formula (I) or salts thereof as an active ingredient.
According to its twentieth aspect, the present invention provides agents for preventing or treating erectile dysfunction which contain at least one of the compounds of the above formula (I) or salts thereof as an active ingredient.
According to its twenty first aspect, the present invention provides agents for preventing or treating female sexual dysfunction which contain at least one of the compounds of the above formula (I) or salts thereof as an active ingredient.
Preferably, a pharmaceutical composition of the present invention is administered to the patient by a dosage form of oral, intranasal, intraurethral, transcutaneous or transmucomembranous preparations. More preferably, oral, intranasal or intraurethral preparations are used.